Crisaborole Crystal Forms for Stability and Bioavailability
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Solution Overview
Problem
There is a lack of reported crystal forms of crisaborole, a boron-containing compound used for treating psoriasis and allergic dermatitis, which hinders the development of pharmaceutical products with optimal physical and chemical characteristics such as stability and bioavailability.
Innovation Solution
Four stable crystal forms of crisaborole are identified and characterized by X-ray powder diffraction patterns, along with methods for their preparation, including dissolution in volatile solvents and suspension in mixed solvents, to produce crystals with desired properties like low moisture absorption and homogeneous particle size distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of information
If no crystal forms are reported for crisaborole, then there is insufficient information for pharmaceutical development, but comprehensive screening requires significant time and resources
Solution Approach 1:
The patent performs preliminary crystal form screening and characterization work in advance, identifying four distinct crystal forms with their specific X-ray diffraction patterns, solubility data, and stability characteristics. This preliminary action provides ready-to-use crystal form information that eliminates the need for time-consuming screening during pharmaceutical development.
2Reliability
If conventional polycrystalline forms are used, then manufacturing is simpler, but stability and bioavailability are insufficient
Solution Approach 1:
The patent identifies and characterizes four distinct crystal forms of crisaborole, each with specific X-ray diffraction patterns and physical properties. By selecting appropriate crystal forms based on their characterized parameters (solubility, stability, moisture absorption), the patent optimizes both stability and manufacturability without requiring complex manufacturing processes.
3Reliability
If crystal forms with high solubility are selected, then bioavailability improves, but storage stability may deteriorate
Solution Approach 1:
The patent characterizes four crystal forms with different solubility and stability profiles. Crystal form I and II offer high solubility for improved bioavailability, while crystal form III and IV provide enhanced storage stability. This parameter-based characterization enables selective optimization of the solubility-stability trade-off based on specific pharmaceutical needs.
Solution Approach 2:
The patent performs preliminary characterization of multiple crystal forms' solubility and stability properties in advance. This allows formulators to select the appropriate crystal form for the intended application (high bioavailability vs. long-term storage) without experiencing unexpected performance issues during product development.
4Adaptability or versatility
If multiple crystal forms are characterized, then selection flexibility increases, but analysis and characterization complexity increases
Solution Approach 1:
The patent systematically characterizes four crystal forms using standardized analytical methods (X-ray diffraction, solubility testing, stability assessment). Each crystal form is defined by specific measurable parameters, creating a clear framework for comparison and selection. This parameter-based approach simplifies the complexity of having multiple crystal forms by providing objective criteria for selection.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystal forms exhibit improved stability, solubility, and storage stability, preventing crystal transitions, and are suitable for pharmaceutical formulations, enhancing the therapeutic effectiveness and shelf life of crisaborole-based medicines.
Implementation Method 1
With Cu—Kα irradiations, the X-ray powder diffraction of the crystal form I has the characteristic peaks at the diffraction angles 2θ: 15.3°±0.2°, 26.1°±0.2°, 14.1°±0.2°
Implementation Method 2
the X-ray powder diffraction of the crystal form I has the characteristic peaks at the diffraction angles
Implementation Method 3
solids of crisaborole in free form are dissolved in a single volatile solvent until the resultant mixture is clear
Implementation Method 4
the resultant mixture performs volatile crystallization, to produce solids of crystal form I
Implementation Method 5
the resultant mixture performs volatile crystallization
Implementation Method 6
the suspension is stirred, subjected to centrifugal separation, and dried, to produce the solids of crystal form I
Implementation Method 7
the suspension is stirred, subjected to centrifugal separation, and dried, to produce the solids of crystal form I
Data Source
AI summary
The present invention relates to four crystal forms of crisaborole in free form and the preparation method thereof. The present invention also relates to the pharmaceutical composition containing the crystal forms and the use thereof.